scholarly journals The divergent effects of CDPPB and cannabidiol on fear extinction and anxiety in a predator scent stress model of PTSD in rats.

2019 ◽  
Author(s):  
John Shallcross ◽  
Peter Hamor ◽  
Allison Bechard ◽  
Madison Romano ◽  
Lori Knackstedt ◽  
...  
Keyword(s):  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Fear Extinction ◽  
Post Traumatic Stress ◽  
Pharmacological Agents ◽  
Phenotypic Differences ◽  
General Anxiety ◽  
Plus Maze ◽  
Response Performance ◽  
Predator Threat

Post-traumatic stress disorder (PTSD) is a disorder with no clear FDA-approved treatments that reduce symptoms in the majority of patients. PTSD individuals possess an impaired capacity for extinguishing fear memory associations. As such, considerable focus has been given to the development of extinction-enhancing pharmacological agents to be used in combination with PTSD treatments. Here we use a predator-threat animal model of PTSD to test the ability of two compounds to enhance contextual fear extinction and reduce anxiety. Mirroring the heterogeneity observed in human response to trauma, an exposure to predator threat, including the fox odor TMT, have been shown to induce long-term changes in anxiety behavior in only subsets of susceptible rats. Here, two weeks following a ten-minute exposure to a predator odor, rats were classified into stress-Susceptible (Sus) and stress-Resilient (Res) phenotypes using cut-off behavioral criteria for elevated plus maze and acoustic startle response performance. One week following classification, Sus rats underwent three days of context fear extinction. We found that Sus rats increased freezing from day one to day two. Treatment with the mGlu5 positive allosteric modulator CDPPB, but not the phytocannabinoid cannabidiol (CBD), prior to sessions resulted in reduced freezing. CDPPB administration resulted in an increase of Fos immunoreactive cells in the medial prefrontal cortex, indicative of increased neuronal activity. Finally, we used the light-dark box test to measure phenotypic differences and the effects of CDPPB and CBD on unconditioned anxiety two weeks after classification. We found that Res rats showed less anxiety compared to Sus rats, and that CBD, but not CDPPB, administered prior to testing was anxiolytic in Sus rats. Taken together, the present data indicate that mGlu5 PAMs such as CDPPB hold promise for treating human PTSD patients as they enhance extinction of fear without increasing general anxiety. Polytherapy with medications such as CBD may be necessary in order to attenuate general anxiety and future directions will explore this hypothesis.

scholarly journals Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long-term effects of a single predator scent stress exposure

2020 ◽  
Author(s):  
John Shallcross ◽  
Lizhen Wu ◽  
Lori A. Knackstedt ◽  
Marek Schwendt
Keyword(s):  
Mrna Expression ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Behavioral Flexibility ◽  
Sprague Dawley ◽  
Long Term Effects ◽  
Post Traumatic Stress ◽  
Specific Expression ◽  
Contextual Fear ◽  
As Stress

AbstractPost-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety, and impaired fear extinction. To model the heterogeneity of PSTD behavioral responses, we exposed Sprague-Dawley rats to predator scent stress (TMT) once for 10 minutes and then tested for anxiety-like behavior 7 days later using the elevated plus-maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress-Susceptible, and rats exhibiting behavior no different from unstressed Controls were classified as stress-Resilient. Our previous findings revealed increased mRNA expression of mGlu5 in the amygdala and PFC and CB1R mRNA in the amygdala of Resilient rats. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and cell-type-specific expression of these genes in Resilient rats. We found higher mRNA expression of mGlu5 in the BLA, IL, and PL, and CB1R in the BLA of Resilient rats relative to Controls. Using dual-labeled FISH we determined that mGlu5 and CB1R mRNA increases were limited to vGlut+ cells. To test the necessity of mGlu5 receptor activity for attenuating contextual fear, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. MTEP increased contextual fear on the day of administration, which extinguished over the course of two additional un-drugged sessions. These results suggest that an enhanced mGlu5 expression within BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations.

scholarly journals Oxytocin and Fear Memory Extinction: Possible Implications for the Therapy of Fear Disorders?

2021 ◽  
Vol 22 (18) ◽  
pp. 10000
Author(s):  
Elisabetta Baldi ◽  
Alessia Costa ◽  
Barbara Rani ◽  
Maria Beatrice Passani ◽  
Patrizio Blandina ◽  
...  
Keyword(s):  
Conditioned Fear ◽  
Brain Structures ◽  
Brain Regions ◽  
Fear Extinction ◽  
Post Traumatic Stress ◽  
Pharmacological Agents ◽  
Memory Extinction ◽  
Post Traumatic ◽  
Psychiatric Conditions ◽  
Fear And Anxiety

Several psychiatric conditions such as phobias, generalized anxiety, and post-traumatic stress disorder (PTSD) are characterized by pathological fear and anxiety. The main therapeutic approach used in the management of these disorders is exposure-based therapy, which is conceptually based upon fear extinction with the formation of a new safe memory association, allowing the reduction in behavioral conditioned fear responses. Nevertheless, this approach is only partially resolutive, since many patients have difficulty following the demanding and long process, and relapses are frequently observed over time. One strategy to improve the efficacy of the cognitive therapy is the combination with pharmacological agents. Therefore, the identification of compounds able to strengthen the formation and persistence of the inhibitory associations is a key goal. Recently, growing interest has been aroused by the neuropeptide oxytocin (OXT), which has been shown to have anxiolytic effects. Furthermore, OXT receptors and binding sites have been found in the critical brain structures involved in fear extinction. In this review, the recent literature addressing the complex effects of OXT on fear extinction at preclinical and clinical levels is discussed. These studies suggest that the OXT roles in fear behavior are due to its local effects in several brain regions, most notably, distinct amygdaloid regions.

scholarly journals The Organizational Role of Testicular Hormones and the Androgen Receptor in Anxiety-Related Behaviors and Sensorimotor Gating in Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1572-1581 ◽  
Author(s):  
Damian G. Zuloaga ◽  
Cynthia L. Jordan ◽  
S. Marc Breedlove
Keyword(s):  
Androgen Receptor ◽  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Sensorimotor Gating ◽  
Male Rats ◽  
Treatment Groups ◽  
Plus Maze ◽  
Neonatal Castration

Abstract Perinatal exposure to testosterone (T), which can act upon both the androgen receptor (AR) and, via aromatization of T into estrogens, upon estrogen receptors, organizes many adult behaviors in rodents. We compared behaviors in wild-type (WT) male rats and AR-deficient rats with the testicular feminization mutation (Tfm), which on the day of birth were either gonadectomized (Neo-Gdx) or sham operated. In adulthood, all rats were either gonadectomized or sham operated and implanted with T capsules to equilibrate circulating androgens. In each of four tests of behavior related to anxiety (open field, novel object exposure, light/dark box, and elevated plus maze), Neo-Gdx rats showed decreased indices of anxiety and increased activity compared with rats sham operated on the day of birth, with no differences between WT or Tfm males within treatment groups. These results indicate that testicular hormones act in development to increase adult indices of anxiety and decrease activity in males and that functional ARs are not required for this effect. Acoustic startle response was also reduced by Neo-Gdx, suggesting that postnatal testicular secretions potentiate this behavior as well. Adult corticosterone levels and sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, were increased by neonatal castration in both WT and Tfm rats. These findings indicate a role of T before adulthood in the organization of anxiety-related behaviors, activity, the hypothalamic-pituitary-adrenal axis, and sensorimotor gating in rats, all of which appears to be AR independent.

scholarly journals Caffeine alters the behavioural and body temperature responses to mephedrone without causing long-term neurotoxicity in rats

2016 ◽  
Vol 30 (7) ◽  
pp. 698-706 ◽  
Author(s):  
Sinead E Shortall ◽  
A Richard Green ◽  
Kevin CF Fone ◽  
Madeleine V King
Keyword(s):  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Brain Regions ◽  
Temperature Changes ◽  
Plus Maze ◽  
Psychoactive Effects ◽  
Acute Adverse Effect ◽  
Temperature Responses

Administration of caffeine with 3,4-methylenedioxymethamphetamine (MDMA) alters the pharmacological properties of MDMA in rats. The current study examined whether caffeine alters the behavioural and neurochemical effects of mephedrone, which has similar psychoactive effects to MDMA. Rats received either saline, mephedrone (10 mg/kg), caffeine (10 mg/kg) or combined caffeine and mephedrone intraperitoneally twice weekly on consecutive days for three weeks. Locomotor activity (days 1 and 16), novel object discrimination (NOD, day 2), elevated plus maze (EPM) exploration (day 8), rectal temperature changes (day 9) and pre-pulse inhibition (PPI) of acoustic startle response (day 15) were assessed. Seven days after the final injection, brain regions were collected for the measurement of 5-hydroxytryptamine (5-HT), dopamine and their metabolites. Combined caffeine and mephedrone further enhanced the locomotor response observed following either drug administered alone, and converted mephedrone-induced hypothermia to hyperthermia. Co-administration also abolished mephedrone-induced anxiogenic response on the EPM, but had no effect on NOD or PPI. Importantly, no long-term neurotoxicity was detected following repeated mephedrone alone or when co-administered with caffeine. In conclusion, the study suggests a potentially dangerous effect of concomitant caffeine and mephedrone, and highlights the importance of taking polydrug use into consideration when investigating the acute adverse effect profile of popular recreational drugs.

scholarly journals Genetic Alteration of Anxiety and Stress-Like Behavior in Mice Lacking CaMKIV

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-22 ◽  
Author(s):  
Fanny WF Shum ◽  
Shanelle W Ko ◽  
Yong-Seok Lee ◽  
Bong-Kiun Kaang ◽  
Min Zhuo
Keyword(s):  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Emotional Behavior ◽  
Dark Light ◽  
Calcium Calmodulin Dependent ◽  
Plus Maze ◽  
Element Binding Protein ◽  
Dependent Protein ◽  
Cyclic Amp Response Element

Calcium-calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the major transcription factor cyclic AMP-response element binding protein (CREB), which plays a role in emotional behavior. Here, CaMKIV knockout mice ( CaMKIV−/−) were tested in a battery of stress and anxiety-related behavioral tests, to determine if CaMKIV plays a role in emotional behavior. CaMKIV−/−exhibited a decrease in anxiety-like behavior in both the elevated plus maze and dark-light emergence tests when compared to wild-type mice. Both the acoustic startle response and prepulse inhibition of startle were decreased with the deletion of CaMKIV. In addition, CaMKIV−/− mice displayed a lack of stress-induced analgesia following restraint or cold swim stress. Our results demonstrate a key role for CaMKIV in anxiety and stress-related behavior.

Acoustic startle response in rats predicts inter-individual variation in fear extinction

2017 ◽  
Vol 139 ◽  
pp. 157-164 ◽  
Author(s):  
Amanda S. Russo ◽  
Ryan G. Parsons
Keyword(s):  
Individual Variation ◽  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Fear Extinction

scholarly journals Suppressed acoustic startle response in traumatic brain injury masks post-traumatic stress disorder hyper-responsivity

Neuroreport ◽  
2018 ◽  
Vol 29 (11) ◽  
pp. 939-944 ◽  
Author(s):  
Grant M. Liska ◽  
Jea-Young Lee ◽  
Kaya Xu ◽  
Paul R. Sanberg ◽  
Cesario V. Borlongan
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Post Traumatic Stress Disorder ◽  
Traumatic Stress ◽  
Startle Response ◽  
Stress Disorder ◽  
Acoustic Startle ◽  
Acoustic Startle Response ◽  
Post Traumatic Stress ◽  
Post Traumatic

The Acoustic Startle Response and Disruption of Aiming. 2. Modulation by Forewarning and Preliminary Stimuli

1989 ◽  
Author(s):  
John A. Foss ◽  
James R. Ison ◽  
James P. Torre ◽  
Wansack Jr ◽  
Samuel
Keyword(s):  
Startle Response ◽  
Acoustic Startle ◽  
Acoustic Startle Response
Sign in / Sign up

Export Citation Format

Share Document